EP 0196132 discloses different procedures for the preparation of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (I), which comprise cyclization of different intermediates by intermolecular condensation reaction among different functional groups to provide 2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one system. Most of these procedures hold in common the use of very complex intermediates and the implementation of problematic reactions in the final synthesis steps that have necessarily an influence on the total cost of the final process.
In EP 0196132, 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (I) may also be prepared by another procedure that comprises formation of a C—N bond by intermolecular N-alkylation reaction of 6-fluoro-3-(4-piperidinyl)-benzo[d]isoxazole (IV) with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one or analogous derivatives with other leaving groups (V) (Scheme 1).

ES2006888, ES2006889 and ES2050069 disclose different procedures for the preparation of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyirido-[1,2-a]pyrimidin-4-one (I), which hold in common a final intramolecular cyclization stage of different types of closely related intermediates to provide the isoxazole ring present in the required product.

ES2074966 discloses a procedure for the preparation of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyirido-[1,2-a]pyrimidin-4-one (I) based on final cyclization of the piperidine ring by double intermolecular N-alkylation reaction of 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) with a pentane-like derivative containing the benzo[d]isoxazole system and the two leaving groups in positions 1 and 5 of general formula VIII (Scheme 2).

One of the starting materials used in the preparation of intermediate VIII is 4-tetrahydropyrancarbonyl chloride (IX)
which is not commercially available. In addition, the preparation of VIII from IX comprises five steps (ES2074966).
The present invention provides an alternative process for the preparation of 3-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (I), which is illustrated in Scheme 3:

The compound of formula II of the present invention, (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)-acetaldehyde is prepared from 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (X) (the preparation of this compound is described in H. Fujita et al. Ann. Rep. Sankyo Res. Lab. 1977, 29, 75–78).
The enamine of formula III, 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-vinyl}-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one, is obtained from aldehyde II and by condensation with 6-fluoro-3-(4-piperidinyl)-benzo[d]isoxazole of formula IV (the preparation of compound IV is described in ES8405791).
The applicants found out that the enamine of formula III is easily reducible to 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (I) by means of the action of a reducing agent.
Alternatively, the formation of the final product, 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (I), may occur directly and advantageously from (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)-acetaldehyde (II) and 6-fluoro-3-(4-piperidinyl)-benzo[d]isoxazole (IV) under reductive amination conditions in a single-stage synthesis process.
The process described in the present invention combines in a unique way elegance in synthesis and compliance with the requirements for cost, safety and ecology in the production of the active substance risperidone (I). The chemical procedure is easily reproducible on a large scale through simple and high-yield synthesis steps which lead to a high-quality final product.
The compounds of formula II and III have not previously described and form part of this invention.